Gabrielsson, Johan
- Department of Animal Biosciences, Swedish University of Agricultural Sciences
Abstract
In this paper, we derive explicit expressions for the concentrations of ligand L, target R and ligand-target complex RL at steady state for the classical model describing target-mediated drug disposition, in the presence of a constant-rate infusion of ligand. We demonstrate that graphing the steady-state values of ligand, target and ligand-target complex, we obtain striking and often singular patterns, which yield a great deal of insight and understanding about the underlying processes. Deriving explicit expressions for the dependence of L, R and RL on the infusion rate, and displaying graphs of the relations between L, R and RL, we give qualitative and quantitive information for the experimentalist about the processes involved. Understanding target turnover is pivotal for optimising these processes when target-mediated drug disposition (TMDD) prevails. By a combination of mathematical analysis and simulations, we also show that the evolution of the three concentration profiles towards their respective steady-states can be quite complex, especially for lower infusion rates. We also show how parameter estimates obtained from iv bolus studies can be used to derive steady-state concentrations of ligand, target and complex. The latter may serve as a template for future experimental designs.
Keywords
constant-rate infusion protocol; drug disposition; drug-target interaction
Published in
AAPS Journal
2017, volume: 19, number: 3, pages: 772-786
Publisher: SPRINGER
SLU Authors
UKÄ Subject classification
Pharmacology and Toxicology
Publication identifier
- DOI: https://doi.org/10.1208/s12248-016-0031-y
Permanent link to this page (URI)
https://res.slu.se/id/publ/82806